The studies proposed here address the hypothesis that Type I diabetes mellitus (T1D) results from the interaction between inherited susceptibility (with a major locus in the HLA region) and viral disease of diverse etiologies. Congenital rubella (CRS) is a viral disease leading to a remarkable increase in the penetrance of the T1D susceptible genotypes. The studies proposed will take advantage of this very high penetrance and of the existence of a clear etiological agent to determine whether the pancreatic beta cell damage results from direct viral toxicity, from autoimmune damage or from a combination of both. The involvement of HLA variants in the determination of susceptibility will be studied with regard to its influence on the ability of patients to mount effective immune responses against rubella virus and to recognize beta cell specific auto antigens as targets for autoimmune attack. The persistence of rubella virus will be investigated to determine whether this agent's continued presence is a requirement for the disease to become expressed and, if so, whether persistence is itself an HLA-dependent variable. It is now known, however, that HLA-DR2 individuals have adherent cells less able to present rubella virus antigen to primed T-cells and since DR2 is negatively associated with insulin-dependent diabetes in CRS patients, a reduced reactivity to rubella virus, at least at this level, may be itself "protective". Thus, beta cell damage may result as a consequence of a better capacity to recognize and, probably, to react against this virus. The patterns of humoral and cellular responses to rubella viral response are a regular feature of all or some of their genotypes. If it would disclose similar associations with those HLA types, the data would strongly suggest a viral antigen-dependent autoimmune reactivity to the beta cells as the possible mechanisms of the beta cell insufficiency in diabetes, and the controls of the anti-viral antigen recognition as one of the mechanisms of the DR involvement in this susceptibility.